Insulin release mediators

As to be expected from a peptide that has been highly conserved during evolution, NPY has many effects, e.g. in the central and peripheral nervous system, in the cardiovascular, metabolic and reproductive system. Central effects include a potent stimulation of food intake and appetite control [2], anxiolytic effects, anti-seizure activity and various forms of neuroendocrine modulation. In the central and peripheral nervous system NPY receptors (mostly Y2 subtype) mediate prejunctional inhibition of neurotransmitter release. In the periphery NPY is a potent direct vasoconstrictor, and it potentiates vasoconstriction by other agents (mostly via Yi receptors) despite reductions of renal blood flow, NPY enhances diuresis and natriuresis. NPY can inhibit pancreatic insulin release and inhibit lipolysis in adipocytes. It also can regulate gut motility and gastrointestinal and renal epithelial secretion. 

Davani B, Khan A, Hult M, et al. Type 1 1 lbeta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem 2000 275(45) 34841-34844. 

Laychock, S. G. (1983). Mediation of insulin release by cGMP and cAMP in a starved animal model. Mol. Cell. Endocrinol. 32, 157-170. 

Our understanding of the details of these processes will probably increase in the near future, due to the development of better techniques for the determination of intracellular [Ca2+], One example involves the use of the fluorescent indicator quin 2. This allows quantitative determination of [Ca2+] rather than the mere confirmation of increase or decrease in [Ca2+].412,413 Quin 2 binds Ca2+ with high selectivity, and its fluorescence increases more than four-fold upon saturation with Ca2". The indicator is added in a lipophilic form, the tetraacetoxymethyl ester, which is taken up by cells. Hydrolysis within the cells gives quin 2, which will then remain in the cell cytosol without binding to cytoplasmic proteins or uptake into organelles. An example of its use lies in the demonstration that release of insulin was mediated by increase in cytosolic Ca2+ produced by use of the Ca2+-ionophore ionomycin.414... 

Limited data are available on in vitro effects of barium on the endocrine system. Studies done with isolated pancreatic islet cells from mice show barium is transported across the cell membrane and incorporated into organelles, especially the mitochondria and secretory granules (Berggren et al. 1983). Barium was found to increase cytoplasmic calcium consequently, the insulin- releasing action of barium may be mediated by calcium. Barium has also been found capable of stimulating the calcitonin secretion system of the thyroid in pigs (Pento 1979). 

The initial suppression of insulin response is probably mediated through increased epinephrine and sympathetic activity in view of the observation that an infusion of epinephrine can suppress insulin release following a glucose infusion in normal subjects (P2). This effect can be blocked by phentolamine. 

The U2 agonists produce a spectrum of pharmacological effects, some of which are attributable to central effects and others to their action on peripheral receptors in target tissues. Within the CNS, tt2 adrenoceptors mediate sedation, analgesia and decreased output from the sympathetic nervous system. The peripheral effects of 02 agonists include vasoconstriction and impaired insulin release. 

Fig. 18. Effect of glucose on insulin release, glucose oxidation, pentose phosphate shunt, NADH/NAD +, NADPH/NADP"1", GSH/GSSG ratios and Ca + uptake of rat pancreatic islets. In a concentration range up to 16.7 mM, glucose-mediated stimulation of insulin secretion is closely parallelled by increases in glucose oxidation, pentose phosphate shunt activity, the NADH/NAD+, NADPH/NADP+, GSH/GSSG ratios and Ca2+ uptake (Ammon and Wahl, 1994).

Enkephalins and endorphins have been found to stimulate insulin release (Ipp etal., 1978 Hermansen, 1983. Verspohl etal., 1986a). In this connection it was also demonstrated that opioid -receptors do not play a role in pancreatic islets but that the insulinotropic effect of low concentrations of Met-enkephalin is mediated via S-receptors (Verspohl et al., 1986a). 

---